The somatostatin receptor subtype 2 (sstr2) is overexpressed in many neuroendocrine tumours. Hence over the past 30 years, there has been considerable interest in developing high-affinity somatostatin-derived ligands that bind sstr2, notably for radionuclide therapy (Kwekkeboom D J, et al., Semin Nucl Med. 2010, 40:78-88). To diagnose and monitor patients with sstr2-positive tumours, radiotracers based on the somatostatin family of peptides, notably octreotate and octreotide, have been labelled with various radioisotopes for non-invasive imaging (Breeman W A P, et al., Eur J Nucl Med., 2001, 28:1421-1429; Ginj M, et al., Chem Biol., 2006, 13:1081-1090; Antunes P, et al., Bioconjug Chem., 2007, 18:84-92; Kwekkeboom D J, et al., Endocr Relat Cancer., 2010, 17:R53-R73). 111In-diethylenetriaminepentaacetic acid-pentetreotide (Octreoscan™; Mallinckrodt) is the current clinical standard for imaging neuroendocrine tumours (Krausz Y, et al., Clin Endocrinol (Oxf)., 2003, 59:565-573; Buchmann I, et al., Eur J Nucl Med Mol Imaging, 2007, 34:1617-1626; Storch D, et al., J Nucl Med., 2005, 46:1561-1569). 99mTc derivatives such as 99mTc-depreotide (Virgolini I, et al., Cancer Res., 1998, 58:1850-1859) and 99mTc-hydrazinonicotinyl-Tyr3-octreotide have also been used (Gabriel M, et al., J Nucl Med., 2003, 44:708-716) but are not commercialized in North America.
For PET imaging, 68Ga, 64Cu, and 18F along with various radioprosthetics have been conjugated to various octreotide derivatives (Sprague J E, et al., Clin Cancer Res., 2004, 10:8674-8682; Gabriel M, et al., J Nucl Med., 2007, 48:508-518; Guo Y, et al., Bioconjug Chem., 2012, 23:1470-1477; Wester H J, et al., Eur J Nucl Med Mol Imaging, 2003, 30:117-122; Poethko T, et al., J Nucl Med., 2004, 45:892-902; Leyton J, et al., J Nucl Med., 2011, 52:1441-1448, and International Patent Application Publication No. WO2012/118909). Of these, certain 68Ga ligands such as 68Ga-DOTATOC, 68Ga-DOTATATE, and 68Ga-DOTANOC have shown promise for neuroendocrine tumour imaging (Henze M, et al., J Nucl Med., 2001, 42:1053-1056; Kayani I, et al., J Nucl Med., 2009, 50:1927-1932; Poeppel T D, et al., J Nucl Med., 2011, 52:1864-1870) and are used in clinical trials as well as under the local practice of pharmacy, particularly in Europe. Nevertheless, 68Ga-PET imaging is not widely available because of the limited daily availability of 68Ga (˜50 mCi) and the lack of FDA-approved 68Ge/68Ga generators (Banerjee S R, Pomper M G., Appl Radiat Isot., 2013, 76:2-13).
18F-fluoride presents several attractive properties for imaging (Laforest R, Liu X., Q J Nucl Med Mol Imaging, 2008, 52:151-158; Kemerink G J, et al., Eur J Nucl Med Mol Imaging, 2011, 38:940-948) and is produced on a daily basis in large quantities in hundreds of cyclotrons in hospitals and radiopharmacies worldwide. Yet the challenges of labelling peptides with 18F-fluoride are significant: the low chemical reactivity of 18F-fluoride in water (Zhan C-G, Dixon D A., J Phys Chem A., 2004, 108:2020-2029) and short half-life (109.8 min) challenge 18F labeling of peptides that are generally soluble only in water or aqueous cosolvents. Hence, fluoride must be dried and reacted in dry solvents at high temperature to radiolabel a radioprosthetic that is then conjugated to the peptide in at least one additional step. Although such multistep 18F-labeling reactions are commonplace (Chin F T, et al., Mol Imaging Biol., 2012, 14:88-95), the relatively short half-life of 18F-fluoride often impedes the clinical application of multistep reactions, particularly in terms of ensuring specific activity greater than 37 GBq/μmol (>1 Ci/μmol) (Cai H, Conti P S., J Labelled Comp Radiopharm., 2013, 56:264-279). Given these challenges, an sstr2 ligand that is easily labelled with 18F-fluoride in high yield and at high specific activity would facilitate sstr2 imaging by PET. Toward these ends, new 18F-octreotate derivatives, such as 18F-SiFA and Al-18F-NOTA, have been labelled in one step and imaged with relative success (Wangler C, et al., Bioconjug Chem., 2010, 21:2289-2296; Laverman P, et al., Tumour Biol., 2012, 33:427-434; Laverman P, et al., J Nucl Med., 2010, 51:454-461).
Similarly, aryltrifluoroborate prosthetics, when conjugated to various peptides, allow one-step aqueous radiofluorination in high yield and very high specific activity (Liu Z, et al., J Labelled Comp Radiopharm., 2012, 14:491-497; Liu Z, et al., Nucl Med Biol., 2013, 40:841-849; Liu Z, et al., Angew Chem Int Ed., 2013, 52:2305-2307, and International Patent Application Publication No. WO2009/012596).
Another methodology for incorporating 18F into imaging agents that makes use of boron as an acceptor capable of binding several 18F atoms, thus increasing the density of positron emitters in the resulting imaging agent, is described in International Patent Application Publication No. WO2005/0077967 and U.S. Pat. No. 8,114,381.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.